As a mediator of the actions of estrogenic hormones, the estrogen receptor (ER) plays a central role in regulating an array of normal physiological processes involved in the development and function of the reproductive system, as well as many other aspects of health, such as bone density, cardiovascular health, and the like.
It is known that compounds that bind to the ER are potentially useful in the treatment of a wide range of disease states. These include estrogen agonists for the treatment of diseases linked to estrogen deficiency, such as osteoporosis, cardiovascular and neurodegenerative diseases in post-menopausal women, and estrogen antagonists for treatment of breast and uterine cancer. Furthermore, it is known that certain ligands, such as tamoxifen, display mixed agonist/antagonist action, i.e., they are estrogen agonists, estrogen antagonists, or partial estrogen antagonists when binding to the ERs of different tissues.
Estrogen and bisphosphonates are the current agents of choice in preventing osteoporosis or post-menopausal bone loss in women. However, estrogen stimulates the uterus and is associated with an increased risk of endometrial cancer. Although the risk of endometrial cancer is thought to be reduced by concurrent use of a progesterone, there remains concern about possible increased risk of breast cancer with the use of estrogen.
Until recently, it had been assumed that estrogen binds to a single ER in cells, causing conformational changes that result in release from heat-shock proteins and binding of the receptor as a dimer to the so-called “estrogen response element” in the promoter region of a variety of genes. Further, pharmacologists have generally believed that non-steroidal, small molecule ligands compete for binding of estrogen to ER, thus acting as either antagonists or agonists in each tissue where the ER is expressed. Thus, such ligands have traditionally been classified as either pure agonists or antagonists. This interpretation, however, is no longer believed to be correct.
Progress over the last few years has shown that ER associates with co-activators (e.g., SRC-1, CBP, and SRA) and co-repressors (e.g., SMRT and N-CoR) that modulate the transcriptional activity of ER in a tissue-specific and ligand-specific manner. In addition, evidence now suggests that the majority of estrogen-regulated genes do not have a classical estrogen response element. In such cases, ER interacts with the transcription factors critical for the regulation of these genes.
Given the complexity of ER signaling, as well as the various types of tissue that expresses ER and its co-factors, it is currently believed that ER ligands can no longer be classified simply as either pure agonists or antagonists. Therefore, the acronym SERM (selective estrogen receptor modulator) has been coined. SERMs bind to the ER, but may act as an agonist or antagonist of estrogen in different tissues and different genes. For example, two of the most well-known drugs that behave as SERMs are tamoxifen (Astra-Zeneca) and raloxifene (Eli Lilly & Co.). Studies with these two compounds, as well as other SERMs currently in development, have demonstrated that the affinity of a SERM for its receptor, in many cases, does not correlate with the pharmacological effect it elicits. Therefore, ligand binding assays traditionally employed in screening for novel ER modulators have not distinguished between tissue selectivity and agonist/antagonist behavior.
More recently, a second ER, designated ERβ, has been identified and cloned. See Katzenellenbogen, et al., Endocrinology, 138, 861–862 (1997). ERβ and the classical ER, re-named ERα, have significantly different amino acid sequences in the ligand binding domain and carboxy-terminal transactivation domains (˜56% amino acid identity) and only 20% homology in their amino-terminal domain. This suggests that some ligands may have higher affinity for one ER over the other. Further, ligand-dependent conformational changes of the two receptors, and interaction with co-factors, will result in quite different biological actions of a single ligand. In other words, a ligand that acts as an agonist on ERα may very well serve as an antagonist on ERβ. An example of such behavior has been disclosed by Paech, et al., Science, 277, 1508–1510 (1997). ERα and ERβ were shown to signal in opposite ways when complexed with the natural hormone estradiol from AP1 site: with ERα, 17β-estradiol activated transcription, whereas with ERβ, 17β-estradiol inhibited transcription.
ERα and ERβ, have both overlapping and disparate tissue distributions. Tissues that express high levels of ERβ include the prostate, testes, ovaries, and certain regions of the brain.
With the identification of ERβ, and the recognition that ERα and ERβ serve different biological roles, ER-selective modulators would possess significant clinical utility in the treatment or prevention of diseases, disorders, conditions, or symptoms mediated by an ER. In addition, ER-selective modulators that have the capacity to selectively bind to, or activate, the ERα and ERβ subtypes would be useful in elucidating the biology of the two receptors and would assist in the development of estrogen pharmaceuticals with improved tissue selectivity.